Case 23- Pharmacology Flashcards
Osteoarthritis
Traditionally ‘wear and tear’ and ‘degenerative,’ there is loss of cartilage and remodelling of adjacent bone. It’s the most common form of arthritis. Changes in the balance of cartilage degradation and synthesis leads to overall loss of cartilage, there may be treatments in the future targeted at this but at the moment its pain management.
How is pain transmitted
Pain is transmitted by either fast or slow sensory fibres into the spinal cord and then upwards to the thalamus to generate the perception of pain. You have the fast pain response and inflammatory factors are released locally which heighten the pain response
Site of analgesic pain and their corresponding pain killers
• Perception of pain= Alpha2- agonists/ COX-2 inhibitors/ Paracetamol, Ketamine, Gabapentine, Neostigimine
• Modulation of pain (in the spinal cord)- Epidural opioids, subarachnoid opioids, ketamine
• Transmission of pain- Epidural/intrathecal local anaestethetics
• Local response to pain- Local anaesthetics (block transmission along pain fibres), NSAIDs (reduce inflammation), COX-2 inhibitors
• Thalamus and cortex- systemic opioids
Opioids act centrally and in the spinal cord. They suppress signalling, the strongest type of analgesic. Contains more than 20 alkaloids, one of the alkaloids is named morphine
Opioid signalling
Opioid drugs use endogenous signalling pathways. Opioid signalling is widespread but dispersed, throughout the CNS. The most important regions are the spinal cord where it interacts with the Nociceptive DRG neuron and the ascending pain pathway. The other major area is the Periaqueductal gray which has a major role in the transferral of the pain signals throughout the brain
Endogenous opioid receptor ligands- made of ligands (medication)
- Endorphin= agonist for the mu opioid receptor, has an analgesic role. The majority of opioids used are selective for the Mu opioid receptor
- Enkephalin= agonist for the delta opioid receptor, has roles in analgesia and mood
- Dynorphin= agonist for the kappa opioid receptor, has roles in analgesia and addiction
Opioid receptors are G protein coupled receptors
- All opioid receptors are seven transmembrane spanning proteins that couple to pertussis sensitive inhibitory G proteins
- The ligand binds the G-protein coupled opioid receptor. We have activation and signalling by the receptors mediated by the heteronormic G-protein. Opioid receptors desensitise rapidly which is driven by the internalisation of the receptor, so the receptor can not be subsequently activated
- Desensitisation to opioids is driven by the internalisation of the opioid receptors so there is less activation of the pathway
- Three different classes= Mu (main target of analgesics), Delta, Kappa
- Gα and Gβγ subunits dissociate to act on various intracellular effector pathways, especially Gi: (reduce cAMP).
Opioid mediated analgesia- spinal and supra-spinal
- Opioid receptors are expressed on nerve endings in spinal cord neurons (μ receptors), and in pain-modulating descending pathways (pain “gating”; μ and δ receptors), including the medulla, locus ceruleus, and peri-aqueductal gray.
- This is through the alpha subunit dissociating from the beta-gamma subunit in the G protein, the alpha subunit will then inhibit Adenylate cyclase reducing CAMP levels. Whilst the beta-gamma subunit will interact with Ca+2 and K+ channels. Inhibition of the voltage gated Ca+2 channels pre-synaptically reduce neurotransmitter release
- Opioids also hyperpolarize the membrane of dorsal horn neuron (post-synaptic cells of the pain pathway) by activation of a K+ conductance, through the beta-gamma subunit. This then reduces the rate of firing
- Additional, non-opioid nociceptive modulatory systems in the CNS can have additive effects, (e.g. serotonergic pathways and adrenergic pathways)
- Opioids are inhibitory and reduce the firing of its targets
Short term side effects of opioids
- Analgesia
- Respiratory depression
- Sedation – but unreliable hypnotic
- Euphoria- disinhibition of the dopaminergic pleasure pathways
- Vasodilation
- Bradycardia
- Cough suppression (mechanistically distinct from respiratory depression)
- Miosis (shows little tolerance, and so good indication for opioid use. MEC for miosis is similar to that for analgesia in non-tolerant individuals – due to increased Parasympathetic outflow to the eye)
- Nausea and vomiting (through direct activation of chemoreceptor neurons in area postrema)
- Skeletal muscle hypertonus
- Constipation (previously used as anti-diarrheal)
- Urinary retention
Long term side effects of opioids
Tolerant to analgesic effects, physical dependence
Respiratory depression and opioids
- Most severe and dangerous side effect
- Analgesic and ventilatory effects share common mechanism (Mu opioid receptor), and so have similar dose-dependency. This means tolerant patients are also resistant to respiratory depression.
- Dose dependent depression of the ventilator response to hypercapnia and hypoxia through actions on Mu opioid receptors in the respiratory centers of the medulla. As the drug concentration increases, the rate of respiration slows.
- With increasing dose breathing slows, tidal volume increases then begins to decline, potentially leading to respiratory failure.
- Effects are potentiated by natural sleep, meaning that patients need to be monitored because of the risk of abrupt respiratory depression in patients who appear stable.
- Normal analgesic doses also cause cardiovascular issues – especially bradycardia and vasodilation
Smooth muscle effects- Opioides
- Mu opioid receptors found throughout the enteric nervous system in the plexus of the bowel, the ureters, and in the bladder.
- Opioids stimulate tonic contraction of smooth muscle at all of these sites, while reducing normal propulsive activity.
- Inhibition of normal intestinal secretions and peristalsis leads to excess water absorption in the gut, -> constipation; little tolerance develops, so becomes a significant problem in those taking opiates chronically (like cancer patients).
- Charged quaternary opioid antagonists such as methylnaltrexone are poorly absorbed (and do not cross BBB) can help with this. Reduces effects of opioids in the periphery but still provides analgesic effects
- Opioids cause urinary retention through decrease in bladder detrusor tone, increased urinary sphincter tone, and decreased awareness of bladder distension.
- Major cause of patient morbidity
Codeine -> Morphine and implications:
- Codeine is converted to Morphine in the liver
- CYP2D6 gene highly polymorphic with important variants
- An individual’s highest functioning CYP2D6 allele predicts his/her phenotypic activity and the effect of codeine on them, can be determined through genetic testing
- Poor metabolisers are unable to convert codeine to morphine efficiently and as a consequence may not experience pain relief.
- Normally a tenth of codeine is converted into morphine
- Ultra-rapid metabolisers may metabolize codeine too efficiently leading to morphine intoxication
- People with reduced expression of efflux pumps will have increased expression in the brain and are at higher risk of respiratory depression
CYP2D6 variants can be categorised into:
- Poor metabolizers, PMs, (low or zero activity variants), very little conversion of codeine to morphine
- Normal metabolizers NMs (high or normal activity variants, also called extensive metabolizers), the majority of people
- Intermediate metabolizers IMs
- Ultrarapid metabolizers UMs (multiple gene copy variants), lots of conversion of codeine to morphine
Tramadol
- Tramadol, a phenylpiperidine analogue of codeine with comparable analgesic effect, is thought to work through modulation of serotonin and norepinephrine reuptake, (i.e. as an SNRI!) in addition to its action as a MOR receptor agonist. The SNRI effect is additive to the opioid effect
- A weak opioid
- Although tramadol displays many of the side-effects associated with Mu receptor agonists, it is reported to produce less respiratory depression and fewer gastrointestinal side-effects than pure Mu opioid receptor agonists of comparable analgesic potency. Means higher doses can be given
- However, it also interacts with drugs that inhibit serotonin and noradrenaline reuptake centrally, leading to serotonin syndrome risk.
Buprenorphine
- Buprenorphine acts as a partial agonist at the mu-opioid receptors and as an antagonist at the kappa-opioid receptors.
- Binds with high affinity, but only partially activates the receptor (low efficacy). Can block most μ agonists and leads to withdrawal effects when used in actively opioid dependent person
- This combination of partial mu-receptor agonism and kappa-receptor antagonism makes buprenorphine useful as an analgesic while also providing some abuse deterrence.
- '’Analgesic ceiling’ effect- limit the opioid analgesic effect
- High potentcy, low efficacy – reduce effects of other opioids
- Less respiratory depression compared to other opioids
Methadona
- Methadone is favoured in heroin treatment because, unlike heroin, methadone is a slow onset, long-acting opioid -> does not have the instantaneous narcotic effects of heroin, which is short-acting.
- Similar potency to morphine on Mu opioid receptors centrally and in the periphery. This activity produces the effects common to all mu opioid agonists: analgesia, euphoria, constipation, sedation, respiratory depression, nausea, and miosis.
- Also antagonizes N-methyl-D-aspartate receptors, which may increase its effectiveness in the treatment of neuropathic pain compared with other opioids
- Generally provided as liquid, within clinic, in order to control the drug supply. I.e. you either drink it or not, you cant hide it under your tongue and then sell it.
Opioid pharmacokinetics
- Different routes: oral is slower than iv.
- Oral opioids eg codeine, oxycodone, methadone – delayed release and ADF (abuse deterrent formulas) options have been developed since the opioid epidemic was recognized
- Transdermal e.g. buprenorphine, fentanyl
- IV opioids e.g. morphine, fentanyl
- Epidural e.g. morphine, fentanyl, sufentanyl, pethidine/meperidine
Non opioid analgesics
Have less analgesic properties but are less likely to lead to addiction, NSAID’s interfere with prostaglandin synthesis
What are Prostaglandins converted into
Prostaglandins are made from phospholipids which is converted by phospholipase A into Arachidonic acid. The Arachidonic acid can be converted into Lipoxygenase and Cyclooxygenase. The Lipoxygenase’s can be converted into Leukotrienes, the Cyclooxygenase’s get converted into Prostaglandins which have roles in inflammation and immune signalling
Aspirin
- Aspirin acts through inhibition of synthesis prostaglandins and thromboxanes via inhibition of the enzyme cyclooxygenase 1 (cox1).
- Aspirin inhibits cox 1 by forming an irreversible bond with the enzyme, making it permanently inactive, and platelets themselves are unable to synthesize new proteins.
- Since prostaglandins and thromboxanes are implicated in producing pain, inflammation, fever, excessive blood clotting, and other pathological conditions, virtually all of the therapeutic effects of aspirin and similar drugs can be explained by their ability to inhibit the synthesis of these two eicosanoid classes.
NSAIDS- COX
Regulates normal cell activity and homeostasis. For example, COX-1 enzymes located in the stomach mucosa synthesize prostaglandins that help protect the stomach lining from gastric acid, and COX-1 enzymes in both the stomach and kidneys produce PGs that maintain blood flow. COX-1 is also the enzyme responsible for synthesizing prostaglandins and thromboxanes regulating normal platelet activity. Helps maintain blood flow to the kidneys, so by reducing thromboxanes and prostaglandins you can cause kidney disease
NSAIDS- COX 2 effect and what COX NSAIDs normally act on
- The COX-2 enzyme is active primarily in injured cells—other chemical mediators (cytokines, growth factors) induce the injured cell to synthesize the COX-2 enzyme, and this enzyme then produces prostaglandins that mediate pain and other aspects of the inflammatory response
- Most NSAIDs act on both COX 1 and COX 2; however, celecoxib is selective for only COX 2. Other COX 2 selective drugs were withdrawn a few years ago because they were found to increase the risk of MI and stroke. However, COX 2 inhibitors are less likely to cause upper GI bleeding.
